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Diseases of the Immune System

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  • 1. Genes and Disease Diseases of the Immune System Diseases of the Immune System The immune system is a complex and highly developed system, yet its mission is simple: to seek and kill invaders. If a person is born with a severely defective immune system, death from infection by a virus, bacterium, fungus or parasite will occur. In severe combined immunodeficiency, lack of an enzyme means that toxic waste builds up inside immune system cells, killing them and thus devastating the immune system. A lack of immune system cells is also the basis for DiGeorge syndrome: improper development of the thymus gland means that T cell production is diminished. Most other immune disorders result from either an excessive immune response or an 'autoimmune attack'. Asthma, familial Mediterranean fever and Crohn's disease (inflammatory bowel disease) all result from an over-reaction of the immune system, while autoimmune polyglandular syndrome and some facets of diabetes are due to the immune system attacking 'self' cells and molecules. A key part of the immune system's role is to differentiate between invaders and the body's own cells - when it fails to make this distinction, a reaction against 'self' cells and molecules causes autoimmune disease. 1
  • 2. Genes and Disease Diseases of the Immune System Asthma Asthma affects more than 5% of the population of chromosomal architecture to our chromosome 5 site the US, including children. It is a chronic inflamma- on their chromosomes 11, 13, and 18. Further study tory disorder of the airways characterized by cough- of the genes in these areas (and others) of the ing, shortness of breath, and chest tightness. A human genome will implicate specific genes involved variety of "triggers" may initiate or worsen an asthma in asthma and perhaps also suggest related biologi- attack, including viral respiratory infections, exercise, cal pathways that play a role in the pathogenesis of and exposure to irritants such as tobacco smoke. asthma. The physiological symptoms of asthma are a narrow- ing of the airways caused by edema (fluid in the intracellular tissue space) and the influx of inflamma- tory cells into the walls of the airways. Asthma is a what is known as a "complex" heri- table disease. This means that there are a number of genes that contribute toward a person's suscepti- bility to a disease, and in the case of asthma, chro- mosomes 5, 6, 11, 14, and 12 have all been implicated. The relative roles of these genes in asthma predisposition are not clear, but one of the most promising sites for investigation is on chromo- some 5. Although a gene for asthma from this site has not yet been specifically identified, it is known that this region is rich in genes coding for key molecules in the inflammatory response seen in asthma, including cytokines, growth factors, and growth factor receptors. The search for specific asthma genes is ongo- ing. Assisting in this international human effort are model organisms such as mice, which have similar Important Links Gene sequence Genome view see gene locations Entrez Gene collection of gene-related information BLink [www.ncbi.nlm.nih.gov/sutils/blink.cgi?pid=4501969&org=1] related sequences in different organisms The literature Research articles online full text Books online books section OMIM catalog of human genes and disorders Websites Global initiative for asthma [www.ginasthma.com:80/] a project conducted in collaboration with the National Heart, Blood and Lung Institute, NIH, and the World Health Organization National Heart, Blood and Lung Institute [www.nhlbi.nih.gov/health/public/lung/index.htm#asthma] information on asthma MEDLINEplus [www.nlm.nih.gov/medlineplus/asthma.html] links on asthma compiled by the National Library of Medicine 2
  • 3. Genes and Disease Diseases of the Immune System Ataxia telangiectasia The first signs of ataxia telangiectasia (A-T) usually sufferers is likely to be helped by harnessing the appear in the second year of life as a lack of balance power of yeast genetics, which allows more rapid and slurred speech. It is a progressive, degenerative and systematic study of the pathways affected by an disease characterized by cerebellar degeneration, ATM mutation. immunodeficiency, radiosensitivity (sensitivity to radiant energy, such as x-ray), and a predisposition to cancer. Back in 1988 the gene responsible for A-T was mapped to chromosome 11. The subsequent identi- fication of the gene proved difficult; it was 7 more years until the human ATM gene was cloned. The diverse symptoms seen in A-T reflect the main role of ATM, which is to induce several cellular responses to DNA damage. When the ATM gene is mutated, these signaling networks are impaired, and so the cell does not respond correctly to minimize the damage. Some of the ATM-dependent signaling pathways are found in yeast. Because these pathways appear to be conserved throughout evolution, they are likely to be central to the DNA damage response. Research into finding an effective therapy for A-T Important Links Gene sequence Genome view see gene locations Entrez Gene collection of gene-related information BLink [www.ncbi.nlm.nih.gov/sutils/blink.cgi?pid=4502267&org=1] related sequences in different organisms The literature Research articles online full text Books online books section OMIM catalog of human genes and disorders Websites The A-T Children's Project [www.atcp.org/] support and research information GeneClinics [www.geneclinics.org/profiles/ataxia-telangiectasia/] a medical genetics resource 3
  • 4. Genes and Disease Diseases of the Immune System Autoimmune polyglandular syndrome The endocrine system is responsible for the release they isolated a novel gene, which they called AIRE of hormones into the blood or lymph. Deficiencies in (autoimmune regulator). Database searches the endocrine system can be caused by infection, revealed that the protein product of this gene is a infarction, or a tumor destroying all or a large part of transcription factor—a protein that plays a role in the the gland. However, the activity of an endocrine regulation of gene expression. The researchers organ is most often depressed as a result of an showed that mutations in this gene are responsible autoimmune reaction that ultimately results in partial for the pathogenesis of APS1. or complete destruction of the gland. Autoimmune The identification of the gene defective in APS1 disease affecting one organ is frequently followed by is the first step toward developing tests that will be the impairment of other glands, resulting in multiple able to genetically diagnose the disease. Further endocrine failure. investigations of the gene and its function should Autoimmune polyglandular syndrome type I also facilitate finding a potential treatment for the (APS1, also called APECED) is a rare autosomal disease as well as increasing our general under- recessive disorder that maps to human chromosome standing of the mechanisms underlying other 21. At the end of 1997, researchers reported that autoimmune diseases. Important Links Gene sequence Genome view see gene locations Entrez Gene collection of gene-related information BLink [www.ncbi.nlm.nih.gov/sutils/blink.cgi?pid=4557291&org=1] related sequences in different organisms The literature Research articles online full text Books online books section OMIM catalog of human genes and disorders Websites American Autoimmune Related Diseases Association [www.aarda.org/] research and patient support 4
  • 5. Genes and Disease Diseases of the Immune System Burkitt lymphoma Burkitt lymphoma results from chromosome translocations that involve the Myc gene. A chromo- some translocation means that a chromosome is broken, which allows it to associate with parts of other chromosomes. The classic chromosome translocation in Burkitt lymophoma involves chromo- some 8, the site of the Myc gene. This changes the pattern of Myc's expression, thereby disrupting its usual function in controlling cell growth and prolifera- tion. We are still not sure what causes chromosome translocation. However, research in model organ- isms such as mice is leading us toward a better understanding of how translocations occur and, Burkitt lymphoma is a rare form of cancer predomi- hopefully, how this process contributes to Burkitt nantly affecting young children in Central Africa, but lymphoma and other cancers such as leukemia. the disease has also been reported in other areas. The form seen in Africa seems to be associated with infection by the Epstein–Barr virus, although the pathogenic mechanism is unclear. Important Links Gene sequence Genome view see gene locations Entrez Gene collection of gene-related information BLink [www.ncbi.nlm.nih.gov/sutils/blink.cgi?pid=12962935&org=1] related sequences in different organisms The literature Research articles online full text Books online books section OMIM catalog of human genes and disorders Websites CancerNet [cancernet.nci.nih.gov/] from the National Cancer Institute, NIH American Cancer Society [www.cancer.org/] research and patient support Oncolink [oncolink.upenn.edu/] comprehensive cancer information from the University of Pennsylvania 5
  • 6. Genes and Disease Diseases of the Immune System Diabetes, type 1 Diabetes is a chronic metabolic disorder that IDDM2 on chromosome 11 and 2) the gene for glu- adversely affects the body's ability to manufacture cokinase (GCK), an enzyme that is key to glucose and use insulin, a hormone necessary for the con- metabolism which helps modulate insulin secretion, version of food into energy. The disease greatly on chromosome 7. increases the risk of blindness, heart disease, kidney Conscientious patient care and daily insulin failure, neurological disease, and other conditions for dosages can keep patients comparatively healthy. the approximately 16 million Americans who are But in order to prevent the immunoresponses that affected by it. Type 1, or juvenile onset diabetes, is often cause diabetes, we will need to experiment the more severe form of the illness. further with mouse models of the disease and Type 1 diabetes is what is known as a 'complex advance our understanding of how genes on other trait', which means that mutations in several genes chromosomes might add to a patient's risk of dia- likely contribute to the disease. For example, it is betes. now known that the insulin-dependent diabetes mel- litus (IDDM1) locus on chromosome 6 may harbor at least one susceptibility gene for Type 1 diabetes. Exactly how a mutation at this locus adds to patient risk is not clear, although a gene maps to the region of chromosome 6 that also has genes for antigens (the molecules that normally tell the immune system not to attack itself). In Type 1 diabetes, the body's immune system mounts an immunological assault on its own insulin and the pancreatic cells that manu- facture it. However, the mechanism of how this happens is not yet understood. About 10 loci in the human genome have now been found that seem to confer susceptibility to Type 1 diabetes. Among these are 1) a gene at the locus Important Links Gene sequence Genome view see gene locations LocusLink collection of gene-related information BLink [www.ncbi.nlm.nih.gov/sutils/blink.cgi?pid=4503951&org=1] related sequences in different organisms The literature Research articles online full text Books online books section OMIM catalog of human genes and disorders Websites Patient information on diabetes [www.niddk.nih.gov/health/diabetes/diabetes.htm] from the National Institute of Diabetes and Digestive and Kidney Diseases, NIH Juvenile Diabetes Research Foundation International [http://www.jdf.org/] 'dedicated to finding a cure' American Diabetes Association [www.diabetes.org/default.htm] research and information 6
  • 7. Genes and Disease Diseases of the Immune System DiGeorge syndrome DiGeorge syndrome is a rare congenital (i.e. present but the loss of immune system T-cells (produced by at birth) disease whose symptoms vary greatly the thymus) is more challenging and requires further between individuals but commonly include a history research on recombination and immune function. of recurrent infection, heart defects, and characteris- tic facial features. DiGeorge syndrome is caused by a large dele- tion from chromosome 22, produced by an error in recombination at meiosis (the process that creates germ cells and ensures genetic variation in the off- spring). This deletion means that several genes from this region are not present in DiGeorge syndrome patients. It appears that the variation in the symp- toms of the disease is related to the amount of genetic material lost in the chromosomal deletion. Although researchers now know that the DGS gene is required for the normal development of the thymus and related glands, counteracting the loss of DGS is difficult. Some effects, for example the car- diac problems and some of the speech impairments, can be treated either surgically or therapeutically, Important Links Gene sequence Genome view see gene locations Entrez Gene collection of gene-related information BLink [www.ncbi.nlm.nih.gov/sutils/blink.cgi?pid=13027630&org=1] related sequences in different organisms The literature Research articles online full text Books online books section OMIM catalog of human genes and disorders Websites Information and support [www.kumc.edu/gec/support/digeorge.html] for DiGeorge syndrome GeneClinics [www.geneclinics.org/profiles/22q11deletion/] a medical genetics resource 7
  • 8. Genes and Disease Diseases of the Immune System Immunodeficiency with hyper-IgM Immunodeficiency with hyper-IgM (HIM) is a rare nity, however, cannot be maintained without a bone primary immunodeficiency characterized by the pro- marrow transplant, which is done when a suitable duction of normal to increased amounts of IgM donor is available. antibody of questionable quality and an inability to To see the interactive version of this figure produce sufficient quantities of IgG and IgA. Individ- requires Cn3D [www.ncbi.nlm.nih.gov/Structure/ uals with HIM are susceptible to recurrent bacterial CN3D/cn3d.shtml], a three-dimensional structure infections and are at an increased risk of autoim- viewer. mune disorders and cancer at an early age. In a normal immune response to a new antigen, B cells first produce IgM antibody. Later, the B cells switch to produce IgG, IgA and IgE, antibodies that protect tissues and mucosal surfaces more effec- tively. In the most common form of HIM there is a defect in the gene TNFSF5, found on chromosome X at q26. This gene normally produces a CD40 anti- gen ligand (CD154), a protein on T cells which binds to the CD40 receptor on B and other immune cells. Without CD154, B cells are unable to receive signals from T cells, and thus fail to switch antibody produc- tion to IgA and IgG. The absence of CD 40 signals between other immune cells makes individuals with HIM susceptible to infections by opportunistic organ- isms such as Pneumocystis and Cryptosporidium species. Treatment of HIM mainly consists of regular IV replacement of the missing IgG antibodies and prompt treatment of infections. Long lasting immu- Important Links Gene sequence Genome view see gene locations Entrez Gene collection of gene-related information BLink [www.ncbi.nlm.nih.gov/sutils/blink.cgi?pid=4557433&org=1] related sequences in different organisms The literature Research articles online full text Books online books section OMIM catalog of human genes and disorders Websites Primary immune deficiency [156.40.88.3/publications/pubs/primaryimmunobooklet.htm] National Institute of Allergy and Infectious Diseases, NIH 8
  • 9. Genes and Disease Diseases of the Immune System Leukemia, chronic myeloid Chronic myeloid leukemia (CML) is a cancer of cells to malignant cells. To research the human dis- blood cells, characterized by replacement of the ease, antisense oligomers (short DNA segments) bone marrow with malignant, leukemic cells. Many of that block BCR-ABL were developed that specifically these leukemic cells can be found circulating in the suppressed the formation of leukemic cells while not blood and can cause enlargement of the spleen, affecting the normal bone marrow cell development. liver, and other organs. These and other experimental techniques may lead CML is usually diagnosed by finding a specific to future treatments for CML. chromosomal abnormality called the Philadelphia (Ph) chromosome (see figure), named after the city where it was first recorded. The Ph chromosome is the result of a translocation—or exchange of genetic material—between the long arms of chromosomes 9 and 22 . This exchange brings together two genes: the BCR (breakpoint cluster region) gene on chro- mosome 22 and the proto-oncogene ABL (Ableson leukemia virus) on chromosome 9. The resulting hybrid gene BCR-ABL codes for a fusion protein with tyrosine kinase activity, which activates signal trans- duction pathways, leading to uncontrolled cell growth. A mouse model has been created that develops a CML-like disease when given bone marrow cells infected with a virus containing the BCR-ABL gene. In other animal models, the fusion proteins have been shown to transform normal blood precursor Important Links Gene sequence Genome view see gene locations Entrez Gene collection of gene-related information BLink [www.ncbi.nlm.nih.gov/sutils/blink.cgi?pid=11038639&org=1] related sequences in different organisms The literature Research articles online full text Books online books section OMIM catalog of human genes and disorders Websites Cancer.gov [http://www.cancer.gov/cancerinfo/wyntk/leukemia] from the National Cancer Institute, NIH 9
  • 10. Genes and Disease Diseases of the Immune System Severe combined immunodeficiency Severe combined immunodeficiency (SCID) repre- substrates for this enzyme accumulate in cells. sents a group of rare, sometimes fatal, congenital Immature lymphoid cells of the immune system are disorders characterized by little or no immune particularly sensitive to the toxic effects of these response. The defining feature of SCID, commonly unused substrates, so fail to reach maturity. As a known as "bubble boy" disease, is a defect in the result, the immune system of the afflicted individual specialized white blood cells (B- and T-lymphocytes) is severely compromised or completely lacking. that defend us from infection by viruses, bacteria Some of the most promising developments in and fungi. Without a functional immune system, the search for new therapies for SCID center on SCID patients are susceptible to recurrent infections 'SCID mice', which can be bred deficient in various such as pneumonia, meningitis and chicken pox, genes including ADA, JAK3, and IL2RG. It is now and can die before the first year of life. Though inva- possible to reconstitute the impaired mouse immune sive, new treatments such as bone marrow and system by using human components, so these ani- stem-cell transplantation save as many as 80% of mals provide a very useful model for studying both SCID patients. normal and pathological immune systems in biomed- All forms of SCID are inherited, with as many as ical research. half of SCID cases linked to the X chromosome, passed on by the mother. X-linked SCID results from a mutation in the interleukin 2 receptor gamma (IL2RG) gene which produces the common gamma chain subunit, a component of several IL receptors. IL2RG activates an important signalling molecule, JAK3. A mutation in JAK3, located on chromosome 19, can also result in SCID. Defective IL receptors and IL receptor pathways prevent the proper devel- opment of T-lymphocytes that play a key role in identifying invading agents as well as activating and regulating other cells of the immune system. In another form of SCID, there is a lack of the enzyme adenosine deaminase (ADA), coded for by a gene on chromosome 20. This means that the Important Links Gene sequence Genome view see gene locations Entrez Gene collection of gene-related information BLink [www.ncbi.nlm.nih.gov/sutils/blink.cgi?pid=4557681&org=1] related sequences in different organisms The literature Research articles online full text Books online books section OMIM catalog of human genes and disorders 10
  • 11. Genes and Disease Diseases of the Immune System Websites SCID Factsheet [www.niaid.nih.gov/factsheets/pid.htm] from the National Institute of Allergy and Infectious Diseases, National Institutes of Health 11

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